Chromogranin A (CGA) and chromogranin B (CGB) are large, acidic proteins found in the secretry granules of a wide variety of endocrine and neuroendocrine tissues including the parathyroid. It has been determined that chromogranin A is present in relatively high concentrations in the parathyroid (see Takatsuki et al., J. Biol. Chem., Vol. 256, pp. 2342-2345 (1981) and Cohn et al., Biochemistry, Vol. 20, pp. 4135-4140 (1981)). In addition, it has been determined that chromogranin A is co-secreted with parathyroid hormone in response to changes in extracellular calcium (see Cohn et al., Endocrinology, Vol. 110, pp. 625-630 (1982)).
Although little is known about the function of chromogranins, there is a growing body of evidence that suggests that chromogranins may be precursors for a number of biologically active peptides. Chromogranin A has been shown to inhibit parathyroid hormone secretion in primary cultures of parathyroid cells (see Fasciotto et al., Endocrinology, Vol. 127, pp. 1329-1335 (1990)). In addition, it has been indicated that the amino terminal region of the protein is responsible for this activity (see Drees et al., Endocrinology, Vol. 129, pp. 3381-3387 (1991)). Further, it has been reported that amino terminal peptide CGA.sub.1-40 stimulates secretion of the hormone CGRP and inhibits secretion of calcitonin (see Deftos et al., J. Bone Min. Res., Vol. 5, pp. 989-991 (1990)). However, to date, no chromogranin B peptides have been reported, and no synthetic chromogranin A or chromogranin B peptides have been developed which are capable of inhibiting parathyroid hormone secretion. In addition, no shortened synthetic chromogranin peptides having similar properties to full-length chromogranin peptides (i.e., inhibiting parathyroid hormone secretion) have been developed.
The inventors have not only prepared synthetic chromogranin A peptides which are capable of inhibiting parathyroid hormone secretion, but have synthesized very short chromogranin A peptides which correspond to part of the amino terminal sequence of naturally-occurring chromogranin A, which peptides are capable of inhibiting parathyroid hormone secretion. In addition, the inventors have also developed a shortened synthetic chromogranin B peptide capable of inhibiting parathyroid hormone secretion.
It is therefore an object of this invention to provide shortened synthetic chromogranin peptides capable of inhibiting parathyroid hormone secretion.
It is a further object of this invention to provide a method of treating hyperparathyroidism and parathyroid hyperplasia-associated renal failure utilizing shortened synthetic chromogranin peptides capable of inhibiting parathyroid hormone secretion.
It is a still further object of this invention to provide a method of preventing or reversing bone resorption, thereby repairing bone fracture utilizing shortened synthetic chromogranin peptides capable of inhibiting parathyroid hormone secretion.
It is another object of this invention to provide a method of treating osteoporosis utilizing shortened synthetic chromogranin peptides capable of inhibiting parathyroid hormone secretion.